Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/695—Silicon compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

• the present invention relates to a medicament for preventing and / or treating vascular disease and cardiac hypertrophy.
• antihypertensive drugs for the treatment of vascular diseases such as arteriosclerosis and cardiac hypertrophy, antihypertensive drugs, antihyperlipidemic drugs,
• PTCA percutaneous coronary angioplasty
• indwelling there is a problem in that restenosis and reocclusion may occur due to vascular damage caused by balloon-expanded stent placement and subsequent smooth muscle proliferation.
• Stents with the ability to release drugs have been proposed for their treatment, but their effectiveness and toxicity remain problematic.
• An object of the present invention is to provide a medicament for preventing and / or treating vascular disease or cardiac hypertrophy, In particular, it is to provide a medicament for preventing and / or treating arteriosclerosis, cerebrovascular disorders, vascular diseases caused by physical damage in blood vessels, and cardiac hypertrophy.
• the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the 4 _ [(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-12-naphthalenyl) power Rubamoyl] benzoic acid and other retinoids have substantially no growth inhibitory effect on vascular endothelial cells, and have a substantial growth inhibitory effect on vascular smooth muscle cells;
• the present inventors have found that the substance has an excellent antiproliferative effect on the neointima of the injured blood vessel, and that it significantly suppresses granulation formation.
• the present invention has been completed based on the above findings.
• the present invention relates to a medicament for the prevention and / or treatment of vascular diseases, which is selected from the group consisting of retinoids and retinoid action regulators, and has a substantially antiproliferative effect on vascular endothelial cells.
• the present invention provides a medicament containing, as an active ingredient, a substance having substantially no proliferation action on vascular smooth muscle cells without having the same.
• the above-mentioned medicament wherein the vascular disease is selected from the group consisting of arteriosclerosis, cerebrovascular disease, and vascular disease caused by physical damage in blood vessels; physical damage in blood vessels
• the above-mentioned medicine in which the vascular disease caused by percutaneous coronary artery angioplasty using an intravascular stent is vascular restenosis and / or reocclusion; an intravascular stent in a form that can be slowly released into the blood Or the above-mentioned medicine contained in a balloon catheter; and the substance which is an active ingredient is 4-[(5,6,7,8-tetrahydro_5,5,8,8-tetramethyl_2-naphthalenyl) pyruvamoyl] benzoic acid
• the above medicine is provided, which is an acid or a salt thereof, or 4 _ [[[3,5_bis (trimethylsilyl) phenyl] potrol] amino] benzoic acid or a salt thereof.
• a medicament for suppressing granulation formation due to physical injury in blood vessels which contains as an active ingredient a substance selected from the group consisting of retinoid and a retinoid action regulator.
• a substance selected from the group consisting of retinoid and a retinoid action regulator which contains as an active ingredient a substance selected from the group consisting of retinoid and a retinoid action regulator.
• the present invention there is provided the above-mentioned medicament, wherein the substance has a substantially growth inhibitory effect on neointima of an injured blood vessel.
• the present invention provides a medicament for suppressing growth, which comprises, as an active ingredient, a substance selected from the group consisting of retinoid and a retinoid action regulator.
• a medicament for preventing and / or treating cardiac hypertrophy which comprises as an active ingredient a substance selected from the group consisting of retinoids and retinoid action regulators, and myocardial fibrosis in cardiac hypertrophy
• the present invention provides a medicament for suppressing the above, which comprises, as an active ingredient, a substance selected from the group consisting of retinoid and a retinoid action regulator.
• the substance which is an active ingredient is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl_2-naphthenyl) pyrubamoyl] benzoic acid or a benzoic acid thereof Or a salt thereof, or the above-mentioned medicament which is 4-[[[[3,5-bis (trimethylsilyl) phenyl] potrol] amino] benzoic acid or a salt thereof.
• the present invention relates to a method for preventing and / or treating a vascular disease, wherein the method is selected from the group consisting of retinoids and retinoid action regulators, and substantially inhibits growth of vascular endothelial cells.
• a method comprising administering to a mammal, including a human, a prophylactically or therapeutically effective amount of a substance having no action and having a substantially growth inhibitory effect on vascular smooth muscle cells;
• a method for suppressing granulation formation due to physical injury comprising a step of administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of retinoid and a retinoid action regulator;
• a method for inhibiting neointimal proliferation in an injury comprising the step of administering to a mammal including humans an effective amount of a substance selected from the group consisting of retinoids and retinoid action regulators. Is done.
• a method for preventing and / or treating cardiac hypertrophy which comprises administering to a mammal, including a human, an effective prophylactic and / or therapeutic amount of a substance selected from the group consisting of retinoids and retinoid action regulators;
• the present invention provides a method for suppressing fibrosis associated with cardiac hypertrophy, which comprises a step of administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of retinoid and a retinoid action regulator.
• an intravascular stent or blood containing the above medicine in a form capable of sustained release in blood is also provided by the present invention.
• FIG. 1 is a graph showing the effect of the drug of the present invention (Am80) on restenosis after stenting.
• retinoic acid and compounds having retinoic acid-like biological activity can be used.
• retinoic acid for example, all'trans (retinoic acid) can be used.
• various vitamin A derivatives synthesized so far for example, benzoic acid derivatives described in JP-A-61-22047 and JP-A-61-76440, and journal “OB * Medicinal” chemistry ( The compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, .2182) can be used as the active ingredient of the medicament of the present invention.
• Retinoid action regulators include 4 _ [5H-2,3- (2,5-dimethyl-2, 5-hexano) —5-methyldibenzo [b, e ] [1,4] diazepine-111-fur] benzoic acid (HX 600) and 4- [1,3-dihydro-7,8_ (2, Benzodiazepine derivatives such as 5- (dimethyl-1,2,5-hexano) -12-oxo-1 2H-1,4-benzodiazepine-15-yl] benzoic acid are known (PCT / JP96 / 2709, International Publication W097 / 11061).
• a substance which itself has a retinoid action can be preferably used.HX600 or LG268 enhances the action of endogenous retinoid pharmacologically administered retinoid. Therefore, these substances can also be preferably used as an active ingredient of the medicament of the present invention. It is also possible to use a compound having an antagonistic action on retinoid in combination for the purpose of regulating the action of retinoid in vivo. Two kinds of active ingredients of medicine in the present invention The above substances may be used in combination.
• the substances exemplified above can be preferably used as the active ingredient of the medicament of the present invention, but the active ingredient of the medicament of the present invention is not limited thereto.
• Acid addition salts include mineral salts such as hydrochloride or hydrobromide, or organic acid salts such as P-toluenesulfonate, methanesulfonate, oxalate, or tartrate be able to.
• the base addition salt include a metal salt such as a sodium salt, a potassium salt, a magnesium salt, or a calcium salt, an ammonium salt, and an organic amine salt such as a triethylamine salt or an ethanolamine salt.
• the form of the salt is not limited to those exemplified above.
• the active ingredient of the medicament of the present invention has one or more asymmetric carbons depending on the type of the substituent
• the optical isomer in a pure form based on such asymmetric carbon is diastereomeric.
• stereoisomers such as isomers
• any mixtures of the stereoisomers, racemates and the like may be used as the active ingredient of the medicament of the present invention.
• any hydrate or solvate of the compound in the form of a free compound or salt may be used as an active ingredient of the medicament of the present invention.
• the medicament of the present invention can be used for prevention and / or treatment of vascular diseases.
• the type of vascular disease is not particularly limited, and examples thereof include cerebrovascular disorders such as arteriosclerosis and cerebrovascular sclerosis, and vascular diseases caused by physical damage in blood vessels.
• retinoide and a retinoid action regulator as active ingredients have substantially no growth-suppressing effect on vascular endothelial cells, It is preferable that the substance has a substantially growth inhibitory effect on cells. It is also preferable that the substance has a differentiation modifying action.
• a representative example of a particularly preferred retinoid having such properties is Am80. Whether a substance "has substantially no growth inhibitory effect on vascular endothelial cells and has a substantially growth inhibitory effect on vascular smooth muscle cells" For example, a person skilled in the art can confirm pharmacologically by the method shown in Example 1.
• Preferred applications of the medicament of the present invention include arteriosclerosis caused by various causes, as well as restenosis or reocclusion of blood vessels after percutaneous coronary angioplasty using an intravascular stent or an intravascular balloon catheter. be able to.
• the substance serving as an active ingredient has an inhibitory action on granulation formation caused by physical injury in blood vessels, and has an effect on neointima of injured blood vessels. It is preferable to have a substantially growth inhibitory effect.
• a representative example of a particularly preferred retinoid having such properties is Am80.
• the medicament of the present invention can be used for prevention and / or treatment of cardiac hypertrophy.
• the medicament of the present invention can suppress the proliferation of fibrous tissue accompanied by inflammation such as interstitial fibrosis accompanying cardiac hypertrophy and fibrosis around coronary arteries.
• fibrous tissue accompanied by inflammation
• interstitial fibrosis accompanying cardiac hypertrophy and fibrosis around coronary arteries.
• the medicament of the present invention includes a substance selected from the group consisting of retinoide and a retinoide action regulator as active ingredients, and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof.
• a substance selected from the group consisting of retinoide and a retinoide action regulator as active ingredients and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof.
• One or more of the above substances may be administered as they are, but preferably, they can be administered in the form of a pharmaceutical composition containing one or more of the above substances and a pharmaceutical additive .
• one or more active ingredients of other pharmaceuticals may be further blended with the above-mentioned pharmaceutical composition to be used as a so-called pharmaceutical composition in the form of a mixture.
• excipient for the formulation is not particularly limited, but may be, for example, excipient, disintegrant or disintegration aid, binder, lubricant, coating agent, pigment, diluent, base, dissolving agent or the like. Dissolution aids, tonicity agents, pH regulators, stabilizers, propellants, adhesives and the like can be mentioned.
• the medicament of the present invention can be administered orally or parenterally.
• Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups, and pharmaceutical compositions suitable for parenteral administration. When Examples thereof include injections, drops, suppositories, inhalants, transdermal absorbents, and transmucosal absorbents.
• the medicament of the present invention can also be used together with angiotensin II receptor antagodist, a calcium antagonist, an ace inhibitor, an anti-high cholesterol drug, or other circulatory drugs.
• the dose of the medicament of the present invention can be appropriately selected according to the type of the target disease, the age and weight of the patient, the severity of the disease, the type of the active ingredient, and the like.
• the dose is 0.1 to 30 mg per adult per day.
• the intravascular stent or the intravascular balloon catheter provided by the present invention can release the above-mentioned substance, which is an active ingredient of the medicament of the present invention, into the blood.
• the placement of the intravascular stent or the intravascular balloon It can suppress granulation formation due to physical injuries in blood vessels that occur during catheterization, and can exert a growth promoting effect on neointima of injured blood vessels.
• the type of base material for forming the stent is not particularly limited, but usually, a metal material such as stainless steel (SUS316, SUS304), nitinol (Ni-Ti alloy), or tantalum, or a polymer material is used. It can be used, and a biodegradable polymer material can also be used.
• the type of the polymer material is not particularly limited as long as it has blood compatibility and does not dissolve in blood.
• the method for producing the stent of the present invention is not particularly limited.
• the stent substrate is a metal
• a polymer coating layer containing the drug of the present invention can be provided on the surface of the stent substrate.
• the drug of the present invention can be blended in molding the polymer material, or a polymer coating layer containing the drug of the present invention can be provided on the surface of the stent substrate. .
• the type of polymer that forms the coating layer is blood-compatible and is not particularly limited as long as it does not dissolve in blood and blood.
• examples of the type include a polyester elastomer and a polyamide elastomer.
• Comps that can respond to stent expansion A polymeric material having a liance is more desirable.
• the concentration of the active ingredient and the concentration of the polymer material in the coating solution can be appropriately selected depending on requirements such as the amount (rate) of the substance eluted from the surface of the coating layer (speed) and the shape of the stent.
• it is desirable to design such that the concentration of the active ingredient in the local area is 10 ⁇ to 1 ⁇ .
• a stent the means for sustained release
• a stent and an artificial organ For example, there is a review by Kamizuma of drug-eluting stents for the prevention of restenosis (Kozutna, K., Coronary intervention, Vol. 1, pp. 58-62) N Others, Catheterization and Cardiovascular Interventions, Vol. 55, pp. 409-417, 2002; New England Journal of Medicine, Vol. 346, 1770-1771 and 177301780, 2002; W002 / 064065, etc., describe specific drug-eluting stents.
• Example 1 Effect on proliferation of endothelial cells and smooth muscle cells
• Rat aortic smooth muscle cells and human umbilical artery endothelial cells were cultured in the presence of 10% fetal calf serum. Noh was measured. The values at each concentration relative to the BrdU incorporation rate without addition of Am80 were tabulated. BrdU incorporation indicates DNA synthesis in proportion to proliferation. Am80 concentration
• a polyethylene tube cuff of a wild type mouse (129SVxC57BL6) femoral artery was placed and injured.
• Am80 was orally administered at 5 mg / kg / day, and after 5 weeks, the appearance and cross section of the injured area were evaluated.
• the area of the neointima of the femoral artery in the tube cuff and the area of granulation tissue around the cuff were measured.
• Table 2 shows the results of the numerical evaluation. The formation of neointima and granulation tissue was significantly reduced in mice treated with Am80 as compared to control (no drug-treated) mice.
• the inside diameter of the heron common iliac artery was measured by intravascular echo (IVUS), and the balloon was expanded to 1-1-1 times the inside diameter, and a stent was placed. After the placement, the inner diameter was measured again by IVUS, and it was confirmed that the change in the inner diameter was 1-1.1 times and that the stent was correctly placed.
• IVUS intravascular echo
• W Table 3 Angiotensin II 3.2 mg / kg / day was administered to mice using an osmotic pump for 2 weeks to create a hypertrophy model. Two weeks later, cardiac hypertrophy, interstitial fibrosis, and fibrosis around the coronary artery were observed. Similarly, mice treated with angiotensin II and Am80 (5 mg / kg / day) for 2 weeks significantly reduced the occurrence of these conditions. W Table 3
• the medicament of the present invention is useful as a medicament for preventing and / or treating vascular diseases such as arteriosclerosis, cerebrovascular disorders, and vascular diseases caused by physical damage in blood vessels, and cardiac hypertrophy. is there.

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• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2003
  • 2003-04-22 CN CNB038091569A patent/CN100553677C/zh not_active Expired - Fee Related
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